title: Nonfunctional NaV1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects.
abstract: Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura. Mutations causing FHM type 3 have been identified in SCN1A, the gene encoding the Nav1.1 Na(+) channel, which is also a major target of epileptogenic mutations and is particularly important for the excitability of GABAergic neurons. However, functional studies of NaV1.1 FHM mutations have generated controversial results. In particular, it has been shown that the NaV1.1-L1649Q mutant is nonfunctional when expressed in a human cell line because of impaired plasma membrane expression, similarly to NaV1.1 mutants that cause severe epilepsy, but we have observed gain-of-function effects for other NaV1.1 FHM mutants. Here we show that NaV1.1-L1649Q is nonfunctional because of folding defects that are rescuable by incubation at lower temperatures or coexpression of interacting proteins, and that a partial rescue is sufficient for inducing an overall gain of function because of the modifications in gating properties. Strikingly, when expressed in neurons, the mutant was partially rescued and was a constitutive gain of function. A computational model showed that 35% rescue can be sufficient for inducing gain of function. Interestingly, previously described folding-defective epileptogenic NaV1.1 mutants show loss of function also when rescued. Our results are consistent with gain of function as the functional effect of NaV1.1 FHM mutations and hyperexcitability of GABAergic neurons as the pathomechanism of FHM type 3.
authors.affiliation: Institute of Molecular and Cellular Pharmacology, Laboratoire d'Excellence Canaux Ioniques d'Intérêt Thérapeutique, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7275, and University of Nice Sophia Antipolis, 06560 Valbonne, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Cestèle
authors.forename: Emanuele
authors.initials: E
authors.lastname: Schiavon
authors.forename: Raffaella
authors.initials: R
authors.lastname: Rusconi
authors.forename: Silvana
authors.initials: S
authors.lastname: Franceschetti
authors.forename: Massimo
authors.initials: M
authors.lastname: Mantegazza
mesh_terms: D000465:Algorithms; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003198:Computer Simulation; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics* / Q000502:physiology; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D020325:Migraine with Aura / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel
keywords: Dravet syndrome; ankyrin; calmodulin; generalized epilepsy with febrile seizures plus; spreading depression